Chlorosulfonic acid as a convenient electrophilic olefin cyclization agent

Article abstract of DOI:10.1016/S0040-4039(03)01635-6

Among several sulfonic acids studied (MeSO₃H, p-TsOH, H₂SO₄, ClSO₃H, FSO₃H), the scarcely used chlorosulfonic acid showed to be an efficient agent for electrophilic olefin cyclizations with internal nucleophilic termination, in a similar manner that is well-established with fluorosulfonic acid. Its availability, lower price and relatively lesser handling problems makes ClSO₃H an advantageous cyclizing agent particularly for high-scale applications. The stereochemical outcome of these cyclizations has been rationalized.

Full text of DOI:10.1016/S0040-4039(03)01635-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6651–6655
Chlorosulfonic acid as a convenient electrophilic olefin
cyclization agent
Pablo J. Linares-Palomino, Sof´ıa Salido, Joaqu´ın Altarejos* and Adolfo Sa´nchez
Departamento de Qu´ımica Inorga´nica y Orga´nica, Facultad de Ciencias Experimentales, Universidad de Jae´n, 23071 Jae´n, Spain
Received 17 June 2003; revised 2 July 2003; accepted 2 July 2003
Abstract—Among several sulfonic acids studied (MeSO3H, p-TsOH, H2SO4, ClSO3H, FSO3H), the scarcely used chlorosulfonic
acid showed to be an efficient agent for electrophilic olefin cyclizations with internal nucleophilic termination, in a similar manner
that is well-established with fluorosulfonic acid. Its availability, lower price and relatively lesser handling problems makes ClSO3H
an advantageous cyclizing agent particularly for high-scale applications. The stereochemical outcome of these cyclizations has
been rationalized.
© 2003 Elsevier Ltd. All rights reserved.
Synthesis of many polycyclic isoprenoids has been
accomplished following the electrophilic polyene
cyclization methodology, the success of which depends
on a combination of factors related to the method of
initiation, the nucleophilicity of the double bonds
involved, and the mechanism of termination.1 Among
the great variety of protonic and Lewis acids used as
external electrophiles to initiate the cyclization, fluoro-
sulfonic acid has shown to be a highly effective reagent
for obtaining fully cyclized compounds in a structurally
and chemically selective, and stereospecific way.2 In
addition, when termination of cyclization is achieved by
an appropriately placed internal nucleophile, the
method has been proved to be also efficient to add a
final heteroatom to the polycyclic skeleton.2b,c In con-
trast to the extensive amount of work developed with
FSO3H much less research has been carried out on
related protonic acids such as chlorosulfonic, sulfuric,
p-toluenesulfonic and methanesulfonic acids, among
others. Thus, the superacid ClSO3H has extensively
been used as a strong sulfating, sulfonating, dehydrat-
ing or chlorinating agent,3,4 but rarely as a cyclizing
agent. It has only been used in the synthesis of several
cyclic terpenoids5 and trans-g-lactonization of two
homoterpenic acids.6 Different cyclizations have been
described using H2SO4,7 p-TsOH8 and MeSO3H,8b,9
most of them involving the generation of a single ring.
Furthermore, in the course of our research on the
synthesis of several odorants10 we were able to learn
about the effectiveness of p-TsOH, in the monocycliza-
tion of alkenols,10c,d and H2SO4 and ClSO3H, in the
bicyclization10b,c and tricyclization10c of polyalkenols
and polyalkenones.
The general information on sulfonic acids is somewhat
confused and contradictory. For example, the weak
Scheme 1.
Keywords: chlorosulfonic acid; sulfonic acids; electrophilic olefin cyclization; benzopyrans; odorants.
* Corresponding author. Tel.: 34-953-002743, fax: 34-953-012141; e-mail: jaltare@ujaen.es
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01635-6

6652
P. J. Linares-Palomino et al. / Tetrahedron Letters 44 (2003) 6651–6655
acid MeSO3H9b has been shown to be as efficient as the
superacid FSO3H;2b the main purpose of this work is to
know the relative cyclizing capabilities of several sul-
fonic acids of increasing acidity (MeSO3H, p-TsOH,
H2SO4, ClSO3H), in comparison with that of the effec-
tive well-known FSO3H. For that, dienols 1 and
dienones 2 were chosen as starting acyclic substrates
because they are able to lead to monocyclic or bicyclic
compounds. The different configuration of the C5ꢀC6
double bond would allow to reach conclusions on
stereospecificity and the presence of internal nucle-
ophilic functional groups enables to combine polyene
and electrophilic heteroatom cyclizations.11 In addition,
the anticipated fully cyclized benzopyran derivatives 3
and 4 seem to be of some interest for the fragrance
industry (Scheme 1).12 Thus, the cyclization reactions of
1 and 2 were conducted with 5 equiv. of sulfonic acid in
2-nitropropane at −78°C.13 The use of a considerable
excess of cyclizing agent at low temperature has been
used in FSO3H-mediated cyclizations and, hence, it was
assumed here as standard cyclization conditions for
both stronger (H2SO4, ClSO3H, FSO3H) and weaker
(MeSO3H, p-TsOH) acids. However, for the latter acids
the reaction temperature had to be changed to room
temperature as lower values led to prolonged reaction
times. In such conditions the cyclizations were normally
completed after 10 min (stronger acids) or 30 min
(weaker acids). As certain amounts of uncharacterized
polymeric compounds always appear in FSO3H cycliza-
tions,2 we decided to add a final filtration through a
silica gel pad of all crude reaction mixtures in order to
know the weight lost in every reaction.13 This practice
gave product recovering in the range of 70–75% for the
three stronger acids and 85–90% for the weaker ones.
The acid cyclizations of alcohols 1 and ketones 2 with
several sulfonic acids are summarized in Table 1. All
final products 3–7 were identified by comparison of
their chromatographic and spectroscopic data with
those reported in the literature.14,15 As may be deduced
from entries 1–5 all cyclization agents mainly promoted
the cyclization of the (E)-alcohol 1a into bicyclic com-
pounds 3, although this conversion was clearly more
effective when ClSO3H (entry 4) and FSO3H (entry 5)
were used. With these latter agents the cyclization of 1a
mainly yielded the trans-fused octahydrobenzopyran
3a, along with a lower amount of the C-2 epimer 3b.
Although MeSO3H, p-TsOH or H2SO4 are compara-
tively less efficient agents in the cyclization of 1a it is
worth noting that reasonable yields of 3 (60.5–73.0%)
were obtained. This means that behaviors of weaker
acids (entries 1–3) under the experimental conditions
used here are not too different from those of the
superacids, although lesser stereoselectivities (certain
amounts (9.5–17.0%) of the cis-fused octahydroben-
zopyrans 3c,d are formed) and selectivities (significant
amounts (26.0–34.0%) of the monocyclic compounds 5
and 7 are formed) have been observed. Before drawing
a final conclusion on the comparative cyclizing abilities
of all these sulfonic acids, the cyclization of the (E)-
ketone 2a was also studied (entries 6–10). Again, a
parallel behavior could be observed, although the ratio
between the trans-fused hexahydrobenzopyran 4a and
the cis-fused stereoisomer 4b was larger in all cases
Table 1. Acid cyclizations of alcohols 1 and ketones 2
Entry
Starting
Cyclization agentb
Products distribution (%)c
materiala
3a
3b
0.5
0.5
24.5
21.0
23.0
3c
3d
1.5
6.0
5.5
4.0
5.0
4a
4b
Others
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
2a
2a
2a
2a
2a
1a
1a
1a
1b
1b
2b
MeSO3H
p-TsOH
H2SO4
ClSO3H
FSO3H
MeSO3H
p-TsOH
H2SO4
ClSO3H
FSO3H
ClSO3Hd
ClSO3He
ClSO3Hf
ClSO3H
FSO3H
ClSO3H
49.5
55.5
26.5
70.0
68.0
15.5
11.0
4.0
-
1a (3.5), 5a (6.5), 5b (3.0), 7 (19.5)
1a (0.5), 5a (5.0), 5b (3.0), 7 (18.0)
1a (3.0), 5a (31.0), 5b (3.0)
1a (1.5), 5a (1.5)
1a (–), 5a (1.0), 5b (1.0)
2a (5.0), 6a (4.0), 6b (2.1)
2a (3.0), 6a (5.5), 6b (4.0)
2a (4.0), 6a (1.9), 6b (3.0)
2a (–), 6a (2.0)
-
50.0
51.0
72.5
92.5
95.0
5.4
2.0
9.0
2.2
3.0
9
10
11
12
13
14
15
16
2a (–), 6a (1.6)
63.0
29.5
22.0
61.3
65.0
22.0
31.0
20.5
6.8
1.0
5.5
10.0
2.9
4.5
5.0
4.5
22.4
16.5
1a (1.0), 5a (3.0), 5b (3.0)
1a (13.0), 5a (12.0), 7 (1.5)
1a (9.0), 5a (21.5), 5b (5.0), 7 (5.0)
1b (0.5), 5a (1.0), 7 (2.5)
1b (–), 5a (1.5)
14.0
2.5
16.0
64.7
2b (–), 6a (2.0), 6b (1.0)
a Alcohols 1a and 1b were prepared by reducing 2a and 2b, respectively, with NaBH4 in MeOH at −10°C; ketones 2a and 2b were obtained by
column chromatography on 20% AgNO3–silica gel of a commercial sample of geranylacetone (2a) which contained ca. 35% of nerylacetone (2b).
b See general procedure in Ref. 13.
c Percentages directly deduced from the GC analysis of the crude reactions. Compounds 3–7 were identified by comparison of their GC retention
times with those from authentic samples prepared in authors’ lab.
d 1a:ClSO3H ratio, 1:2.5; reaction temperature, −78°C; reaction time, 25 min.
e 1a:ClSO3H ratio, 1:2.5; reaction temperature, −45°C; reaction time, 25 min.
f 1a:ClSO3H ratio, 1:2.5; reaction temperature, −17°C; reaction time, 25 min.

P. J. Linares-Palomino et al. / Tetrahedron Letters 44 (2003) 6651–6655
6653
than that observed with 1a. Invariably, ClSO3H (entries
4, 9) seemed to have a closer behavior to FSO3H
(entries 5, 10), justifying previous complementary
results.5,6,10b,10c This allows us to propose that ClSO3H
is a convenient cyclizing agent with a very similar
degree of efficiency as the well-established FSO3H. Fur-
thermore, the considerably lower price of ClSO3H and
relative lesser handling problems16 makes it more
advantageous than FSO3H, particularly for high-scale
applications. In order to improve the experimental use
of ClSO3H we explored different substrate:acid ratios
and reaction temperatures. The 1a:ClSO3H ratio could
be decreased up to 1:2.5 (entry 11) without loosing
efficiency, however, rising temperature (entries 12, 13)
resulted in continuous loss of selectivity; less trans-
fused 3a,b, more cis-fused 3c,d and more monocyclic
compounds (5, 7) were progressively obtained.
Although we have previously shown that ClSO3H may
Figure 1. Proposed mechanism for the acid-mediated cyclization of alcohols 1 and ketones 2.

6654
P. J. Linares-Palomino et al. / Tetrahedron Letters 44 (2003) 6651–6655
perform cyclizations on a stereospecific way10c as
FSO3H,2 we wished to confirm this aspect with 1a.
Thus, the (Z)-alcohol 1b was treated with ClSO3H
using the initial procedure (entry 14) and, surprisingly,
we obtained the same major compound (3a). However,
when the (Z)-ketone 2b was reacted with ClSO3H the
cis-fused hexahydrobenzopyran 4b was stereospecifi-
cally formed in good yield (entry 16).
References
1. Sutherland, J. K. In Polyene Cyclizations; Trost, B. M.;
Fleming, I.; Pattenden, G., Eds.; Comprehensive organic
synthesis; Pergamon Press: Oxford, 1991; Vol. 3, pp.
341–377.
2. For recent and key papers, see: (a) Ungur, N.; Kulcitki,
V.; Gavagnin, M.; Castellucio, F.; Vlad, P. F.; Cimino,
G. Tetrahedron 2002, 58, 10159–10165 and references
cited therein; (b) Vlad, P. F. Pure Appl. Chem. 1993, 65,
1329–1336 and references cited therein; (c) Snowden, R.
L.; Eichenberger, J.-C.; Linder, S. M.; Sonnay, P.; Vial,
C.; Schulte-Elte, K. H. J. Org. Chem. 1992, 57, 955–960.
3. Encyclopedia of Reagents for Organic Synthesis; Paquette,
L. A., Ed.; John Wiley & Sons: Chichester, 1995.
4. Cremlyn, R. J. Chlorosulfonic Acid: A Versatile Reagent;
Royal Society of Chemistry: Cambridge, 2002.
A possible explanation of the observed results is shown
in Figure 1. The bicyclization of alcohols 1 and ketones
2 to give 3 and 4, respectively, seems to occur through
a nonsynchronous process involving prior ring closure
to a cyclohexyl cation as variable amounts of mono-
cyclic compounds (5, 6) are detected in all cases. Thus,
the main formation of the trans-fused octahydroben-
zopyrans 3a,b and hexahydrobenzopyran 4a from 1a
and 2a, respectively, may be rationalized by the genera-
tion of intermediate I while the smaller amounts of the
cis-fused isomers 3c,d and 4b, obtained in the same
reactions, could be explained through the conforma-
tional inversion of that A-ring cation to intermediate II
and subsequent cyclization of the B-ring. In a similar
manner, the cyclization of the (Z)-isomers 1b and 2b
may be justified by a nonsynchronous pathway through
intermediate II, although clear differences have to be
present now as the stereospecificity was lost when alco-
hol 1b was the starting material, also with FSO3H
(entry 15), and conserved when ketone 2b was used.
The explanation based on the isomerization of 1b to 1a
and subsequent bicyclization through intermediate I to
give 3a,b was ruled out because no isomerization was
observed in the recovered starting material of this reac-
tion (entry 14). Other more probable explanation could
be based on the different nucleophilicity of carbonyl
and hydroxyl groups in superacidic medium; thus, the
comparatively less deactivated carbonyl group (2b)
mainly gives the cis-fused isomer 4b by a nonsyn-
chronous process where the intermediate II is rapidly
attacked by the oxygen atom (k1 bigger than k2). How-
ever, in the case of the relatively more deactivated
hydroxyl group (1b) the conformation inversion of the
A-ring cation (intermediate II) occurs faster than the
B-ring closure (k2 bigger than k1) leading to a nonsyn-
chronous process where the most stable trans-fused
isomers 3a,b are obtained. This latter result along with
few FSO3H-mediated cyclizations of monoterpenoids2b
are the only exceptions to the regularities described for
superacid induced cyclizations.
5. Oritani, T.; Yamashita, K. JP 02258773 [Chem. Abstr.
1990, 114, 143747].
6. Imamura, P. M.; Santiago, G. M. P. Synth. Commun.
1997, 27, 2479–2485.
7. For some references, see: (a) Schlummer, B.; Hartwig, J.
F. Org. Lett. 2002, 4, 1471–1474; (b) Erman, M. B.;
Hoffmann, H. M.; Ca´rdenas, C. G. EP 985651 [Chem.
Abstr. 2000, 132, 207981]. For an example of bicycliza-
tion, see: (c) Muntyan, G. E.; Kurbanov, M.; Smit, V. A.;
Semenovskii, A. V.; Kucherov, V. F. Izv. Akad. Nauk
SSSR, Ser. Khim. 1973, 633–639 [Chem. Abstr. 1973, 79,
18869f].
8. For some references, see: (a) Miura, K.; Okajima, S.;
Hondo, T.; Nakagawa, T.; Takahashi, T.; Hosomi, A. J.
Am. Chem. Soc. 2000, 122, 11348–11357; (b) Knuebel,
G.; Bomhard, A.; Market, T. DE 4439574 [Chem. Abstr.
1996, 125, 33910].
9. (a) Anubhav, P. S.; Narula, A. P. S.; Schreiber, W. L. In
Acid Catalyzed Reactions of Cyclic Olefinic Alcohols;
Baser, K. H. C., Ed.; Flavours, fragrances and essential
oils. AREP Publ.: Istanbul, 1995; pp. 78–84. For a tricy-
clization, see: (b) Cassel, J.; Olivero, A.; Bomhard, A. DE
4301555 [Chem. Abstr. 1994, 121, 133953].
10. (a) Castro, J. M.; Salido, S.; Altarejos, J.; Nogueras, M.;
Sa´nchez, A. Tetrahedron 2002, 58, 5941–5949 and refer-
ences cited therein; (b) Linares, P.; Salido, S.; Altarejos,
J.; Nogueras, M.; Sa´nchez, A. In Chlorosulfonic Acid as a
Cyclization Agent for Preparing Cyclic Ether Odorants;
Lanzotti, V.; Taglialatela-Scafati, O., Eds.; Flavour and
fragrance chemistry; Kluwer Academic Publishers: Dor-
drecht, 2000; pp. 101–107 and references cited therein; (c)
Barrero, A. F.; Altarejos, J.; Alvarez-Manzaneda, E. J.;
Ramos, J. M.; Salido, S. J. Org. Chem. 1996, 61, 2215–
2218; (d) Barrero, A. F.; Altarejos, J.; Alvarez-Man-
zaneda, E. J.; Ramos, J. M.; Salido, S. Tetrahedron 1993,
49, 6251–6262.
In conclusion, chlorosulfonic acid is found to accom-
plish electrophilic olefin cyclizations as efficiently as
fluorosulfonic acid and, hence, its protonating
superacid properties should be reevaluated.
11. Harding, K. E.; Tiner, T. H. In Electrophilic Heteroatom
Cyclizations; Trost, B. M.; Fleming, I.; Semmelhack, M.
F., Eds.; Comprehensive organic synthesis, Pergamon
Press: Oxford, 1991; Vol. 4, pp. 363–421.
Acknowledgements
12. Masuda, H.; Mihara, S. JP 6165879 [Chem. Abstr. 1986,
105, 97748x].
We wish to thank the Junta de Andaluc´ıa for financial
support and Dr. Vlad (Moldova Sciences Academy)
and Dr. Snowden (Firmenich S.A.) for their valuable
comments.
13. Acid cyclization of alcohols 1 and ketones 2. General
procedure: To a solution of 2.50 mmol of sulfonic acid
(99.5% MeSO3H, 98.5% p-TsOH·H2O dehydrated
according to Ref. 17, 98% H2SO4, 99% ClSO3H, triple-

P. J. Linares-Palomino et al. / Tetrahedron Letters 44 (2003) 6651–6655
6655
distilled FSO3H) in 2-nitropropane (3 mL) was added
(MeSO3H, p-TsOH) dropwise (H2SO4, ClSO3H, FSO3H)
a solution of 1 or 2 (0.5 mmol) in 2-nitropropane (6 mL)
at room temperature (MeSO3H, p-TsOH) or −78°C
(H2SO4, ClSO3H, FSO3H) under argon. After stirring for
30 min (MeSO3H, p-TsOH) or 10 min (H2SO4, ClSO3H,
FSO3H) at those temperatures a saturated aq. NaHCO3
solution (10 mL) was injected and then further portions
of solid NaHCO3 were added to obtain basic pH. Brine
(20 mL) and Et2O (15 mL) were added and the mixture
extracted with Et2O (3×15 mL). After drying the com-
bined organic layers with anhydrous Na2SO4 and evapo-
ration of the solvent under reduced pressure, a residue
was obtained which was filtered through an SiO2 (70–230
mesh) pad (1 cm width×2 cm high) using a 1:1 hexane–
Et2O mixture (100 mL) as eluent. This solution was
concentrated to dryness, weighed and analyzed directly
by GC.
chromatography. Reference samples of alcohols 5a and
5b were prepared by reducing 6a and 6b, respectively,
with NaBH4 in MeOH at −10°C. Ketones 6a and 6b were
obtained from commercial b-ionone and a-ionone,
respectively, by Raney-Ni induced catalytic hydrogena-
tion.10b,c Pyran 7 was purified from crude reactions of 1a
with MeSO3H and p-TsOH (entries 1 and 2). Spectral
data of all these purified compounds were according to
those reported in the literature.15
15. (a) Ravasio, N.; Leo, V.; Babudri, F.; Gargano, M.
Tetrahedron Lett. 1997, 38, 7103–7106; (b) Sugai, T.;
Yokochi, T.; Watanabe, N.; Ohta, H. Tetrahedron 1991,
47, 7227–7236; (c) Whitfield, F. B.; Stanley, G. Aust. J.
Chem. 1977, 30, 1073–1091.
16. Both superacids are corrosive and have to be handled in
a fume hood with proper protection. However, we have
used ClSO3H for a long time with the same precautions
as with H2SO4 and taking samples from bottles opened to
the air during the process without detecting loss of
efficiency, despite some formation of SO3 (or H2SO4) and
HCl.18
14. Octahydrobenzopyrans 3a–d were purified from several
cyclization crude reactions of 1a and 1b by successive
carefully performed silica gel column chromatographies.
Hexahydrobenzopyran 4a was directly obtained by
stereoselective cyclization of 2a (Table 1, entries 9 and 10)
and the stereoisomer 4b by cyclization of 2b (entry 16)
followed by further purification on silica gel column
17. Perrin, D. D.; Armarego, W. L. F. Purification of Labo-
ratory Chemicals; Pergamon Press: Oxford, 1988.
18. Olah, G. A.; Prakash, G. K. S.; Sommer, J. Superacids;
John Wiley & Sons: New York, 1985.